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FRANKINCENSE vs CANCER






http://news.bbc.co.uk/2/hi/middle_east/8505251.stm

Frankincense: Could it be a cure for cancer?

by

Jeremy Howell

The gift given by the wise men to the baby Jesus probably came across the deserts from Oman. The BBC's Jeremy Howell visits the country to ask whether a commodity that was once worth its weight in gold could be reborn as a treatment for cancer.

Oman's Land of Frankincense is an 11-hour drive southwards from the capital, Muscat.

Most of the journey is through Arabia's Empty Quarter - hundreds of kilometres of flat, dun-coloured desert. Just when you are starting to think this is the only scenery you will ever see again, the Dhofar mountains appear in the distance.

On the other side are green valleys, with cows grazing in them. The Dhofar region catches the tail-end of India's summer monsoons, and they make this the most verdant place on the Arabian peninsula.

Warm winters and showery summers are the perfect conditions for the Boswellia sacra tree to produce the sap called frankincense. These trees grow wild in Dhofar. A tour guide, Mohammed Al-Shahri took me to Wadi Dawkah, a valley 20 km inland from the main city of Salalah, to see a forest of them.

"The records show that frankincense was produced here as far back as 7,000 BC," he says. He produces an army knife. He used to be a member of the Sultan's Special Forces. With a practised flick, he cuts a strip of bark from the trunk of one of the Boswellia sacra trees. Pinpricks of milky-white sap appear on the wood and, very slowly, start to ooze out.

"This is the first cut. But you don't gather this sap," he says. "It releases whatever impurities are in the wood. The farmers return after two or three weeks and make a second, and a third, cut. Then the sap comes out yellow, or bright green, or brown or even black. They take this."

Shortly afterwards, a frankincense farmer arrives in a pick-up truck. He is white-bearded, wearing a brown thobe and the traditional Omani, paisley-patterned turban.

He is 67-year-old Salem Mohammed from the Gidad family. Most of the Boswellia sacra trees grow on public land, but custom dictates that each forest is given to one of the local families to farm, and Wadi Dawkah is his turf.

He has an old, black, iron chisel with which he gouges out clumps of dried frankincense.

"We learnt about frankincense from our forefathers and they learnt it from theirs" he says. "The practice has been passed down through the generations. We exported the frankincense, and that's how the families in Dhofar made their livings."

And what an export trade it was. Frankincense was sent by camel train to Egypt, and from there to Europe. It was shipped from the ancient port of Sumharan to Persia, India and China. Religions adopted frankincense as a burnt offering.

That is why, according to Matthew's Gospel in the Bible, the Wise Men brought it as a gift to the infant Jesus. Gold: for a king. Frankincense: for God. Myrrh: to embalm Jesus' body after death.

The Roman Empire coveted the frankincense trade. In the first century BCE, Augustus Caesar sent 10,000 troops to invade what the Romans called Arabia Felix to find the source of frankincense and to control its production. The legions, marching from Yemen, were driven back by the heat and the aridity of the desert. They never found their Eldorado.

Oman's frankincense trade went into decline three centuries ago, when Portugal fought Oman for dominance of the sea routes in the Indian and the Pacific Oceans.

The Haffa souk in Salalah
Salalah's Haffa souk: The place to buy Omani brands such as Royal Hougari

Nowadays, hardly any Omani frankincense is exported. Partly, this is because bulk buyers, such as the Roman Catholic Church, buy cheaper Somalian varieties. Partly, it is because Omanis now produce so little.

"Years ago, 20 families farmed frankincense in this area," says Salem Mohammed Gidad. "But the younger generation can get well-paid jobs in the government and the oil companies, with pensions. Now, only three people still produce frankincense around here. The trade is really, really tiny!"

Cancer hope

But immunologist Mahmoud Suhail is hoping to open a new chapter in the history of frankincense.

Scientists have observed that there is some agent within frankincense which stops cancer spreading, and which induces cancerous cells to close themselves down. He is trying to find out what this is.

"Cancer starts when the DNA code within the cell's nucleus becomes corrupted," he says. "It seems frankincense has a re-set function. It can tell the cell what the right DNA code should be.

"Frankincense separates the 'brain' of the cancerous cell - the nucleus - from the 'body' - the cytoplasm, and closes down the nucleus to stop it reproducing corrupted DNA codes."

Working with frankincense could revolutionise the treatment of cancer. Currently, with chemotherapy, doctors blast the area around a tumour to kill the cancer, but that also kills healthy cells, and weakens the patient. Treatment with frankincense could eradicate the cancerous cells alone and let the others live.

The task now is to isolate the agent within frankincense which, apparently, works this wonder. Some ingredients of frankincense are allergenic, so you cannot give a patient the whole thing.

Dr Suhail (who is originally from Iraq) has teamed up with medical scientists from the University of Oklahoma for the task.

In his laboratory in Salalah, he extracts the essential oil from locally produced frankincense. Then, he separates the oil into its constituent agents, such as Boswellic acid.

"There are 17 active agents in frankincense essential oil," says Dr Suhail. "We are using a process of elimination. We have cancer sufferers - for example, a horse in South Africa - and we are giving them tiny doses of each agent until we find the one which works."

"Some scientists think Boswellic acid is the key ingredient. But I think this is wrong. Many other essential oils - like oil from sandalwood - contain Boswellic acid, but they don't have this effect on cancer cells. So we are starting afresh."

The trials will take months to conduct and whatever results come out of them will take longer still to be verified. But this is a blink of the eye in the history of frankincense.

Nine thousand years ago, Omanis gathered it and burnt it for its curative and cleansing properties. It could be a key to the medical science of tomorrow.



http://theresanoilforthat.blogspot.com/2012/02/frankincense-and-cancer.html

Frankincense and Cancer

Studies on Frankincense and Cancer


History:

Frankincense trees were considered extremely valuable during ancient times and their location was often a matter of state secret. Egyptians used the incense to fumigate their homes, for ritual incense and the oil for cosmetics. It was used as a holy anointing oil and as a general cure-all for all diseases. It was also used to enhance meditation and elevate spiritual consciousness. History shows it was used for embalming and as a perfume AND formed an important part of the Sabbath day offering. Frankincense or olibanum was mentioned inthe Scriptures over 50 times and is found in the books of Exodus, Leviticus, Numbers, Chronicles, Nehemiah,Song of Solomon, Isaiah, Matthew, and Revelations.

Actions:

The actions of frankincense include anti-inflammatory, anti-tumoral, immune-stimulant, antidepressant and muscle relaxing. It stimulates the limbic system as well as the hypothalamus, pineal and pituitary glands. It is strongly anti-viral, antioxidant, antifungal, antibacterial, antiseptic and expectorant oil. Frankincense has the ability to relax and revitalize at the same time.

Research:

Cancer Research Using Frankincense

There are a few researchers studying the effects of frankincense on various cancers with some degree of success. In vitro effects show inhibition or stimulation of cell proliferation depending on the concentration of frankincense oil in the growth media.

A recent study conducted at the University of Oklahoma showed that frankincense kills bladder cancer cells without harming surrounding tissue.

Studies are showing frankincense to be a strong immune-stimulant with some claiming that frankincense has the ability to repair DNA.

A Chinese study conducted in 2000, indicated that Boswellia has “anti-carcinogenic and anti-tumor activities.” These boswellic acids from frankincense inhibited “a variety of malignant cells” in people suffering from leukemia and brain tumors.

The Cancer Research Institute of the University of Nevada treated cervical cancer with frankincense, in which “there was 72% inhibition and growth of non-cancerous cells.”

Other studies have shown that boswellic acids from frankincense exert anti-prolifertive activity toward a variety of malignant cells.

Another study showed that boswellic acids are potent apoptotic agents to cancer cells and another one shows that Boswellic acids from frankincense gum exhibit potent cytotoxic activity againstCNS tumors.

Why Hasn’t the General Public Heard about This?

It sounds incredulous but the anti-cancerous effects of frankincense has been known for thousands of years. Does it work for everyone? No, but compared to the effects of chemotherapy, frankincense DOES show great promise now and in the future. Frankincense will never be promoted for the breakthrough that it is because there is no money to be made in its promotion. Frankincense is expensive in comparison to other therapeutic grade oils but “cheap” in comparison to drugs like chemotherapy.

Scientists have observed and do agree that there is some agent within frankincense which stops cancer spreading, and which induces cancerous cells to close themselves down. Immunologist Mahmoud Suhail is quoted "Cancer starts when the DNA code within the cell's nucleus becomes corrupted. It seems frankincense has a re-set function. It can tell the cell what the right DNA code should be. Frankincense separates the 'brain' of the cancerous cell - the nucleus - from the 'body' - the cytoplasm, and closes down the nucleus to stop it reproducing corrupted DNA codes."--Currently, with chemotherapy, doctors blast the area around a tumour to kill the cancer, but that also kills healthy cells, and weakens the patient. Treatment with frankincense could eradicate the cancerous cells alone and let the others live.The task now is to isolate the agent within frankincense which, apparently, works this wonder

History Medical Research (Bosellia serrata)

In Ayurvedic medicine Indian frankincense (Boswellia serrata), commonly referred to as "dhoop," has been used for hundreds of years for treating arthritis, healing wounds, strengthening the female hormone system, and purifying the atmosphere from undesirable germs. The use of frankincense in Ayurveda is called "dhoopan". In Indian culture, it is suggested that burning frankincense everyday in house brings good health.

Standardized preparations of Indian frankincense from Boswellia serrata are being investigated in scientific studies as a treatment for chronic inflammatory diseases such as Crohn's disease, ulcerative colitis, and osteoarthritis. Initial clinical study results indicate efficacy of incense preparations for Crohn's disease. For therapy trials in ulcerativecolitis, asthma, and rheumatoid arthritis there are only isolated reports and pilot studies from which there is not yet sufficient evidence of safety and efficacy. Similarly, the long-term effects and side effects of taking frankincense has not yet been scientifically investigated. Boswellic acid in vitro antiproliferative effects on various tumor cell lines (such as melanoma, glioblastomas, liver cancer) are based on induction of apoptosis. A positive effect has been found in the use of incense on the accompanying specimens of brain tumors, although in smaller clinical trials. Some scientists say the results are due to methodological flaws. The main active compound of Indian incense is viewed as being boswellic acid.

As of May 2008 FASEB Journal announced that Johns Hopkins University and the Hebrew University of Jerusalem have determined that frankincense smoke is a psychoactive drug that relieves depression and anxiety in mice. The researchers found that the chemical compound in censole acetate is responsible for the effects.

In a different study, an enriched extract of "Indian Frankincense" (usually Boswellia serrata) was used in a randomized, double-blinded, placebo-controlled study of patients with osteoarthritis. Patients receiving the extract showed significant improvement in their arthritis in as little as seven days. The compound caused no major adverse effects and, according to the study authors, is safe for human consumption and long-term use.

The study was funded by a company which produces frankincense extract, and that the results have not yet been duplicated by another study.

In a study published in March 2009 by the University of Oklahoma Health Sciences Center it was reported that"Frankincense oil appears to distinguish cancerous from normal bladder cells and suppress cancer cell viability

Study: Frankincense may fight some cancers
January 31, 2006

A Virginia Tech scientist says frankincense oil might be useful in treating malignant melanoma -- an aggressive cancer that attacks humans and equines.

Approximately 54,000 malignant melanoma cases are diagnosed annually, according to the American Cancer Society, and there are many similarities between malignant melanoma in horses and malignant melanoma in people.

Recognizing the opportunity for translational research, John Robertson, a professor in the Virginia-Maryland Regional College of Veterinary Medicine at Virginia Tech, has been studying the disease and an experimental treatment involving frankincense oil.

Frankincense is a botanical oil distillate made from fermented plants that contains boswellic acid, a component known to have anti-neoplastic properties.

During a recent presentation before a regional meeting of the American Cancer Society in Roanoke, Va., Robertson -- director of the college's Center for Comparative Oncology -- said he's found the oil has fairly selective anti-tumor activity and doesn't appear to disrupt normal cells."I think this research on frankincense oil suggests that this ancient medicine may have significant modern uses for chemotherapy of non-resectable malignancies," said Robertson.



http://gulfnews.com/news/gulf/oman/oman-researchers-find-cancer-treatment-in-frankincense-1.1251940

Muscat: Omani researchers at the University of Nizwa have succeeded in producing a medicinally important compound from Omani frankincense, luban, for breast cancer treatment.

Dr Ahmad Sulaiman Al Harrasi, holder of the University’s Chair of Oman’s Medicinal Plants and Marine Natural Products, said researchers have succeeded in isolating and enhancing the percentage of AKBA found in the resin of Omani frankincense.

AKBA (beta-boswellic acid, keto-beta-boswellic acid, and acetyl-keto-beta-boswellic acid) has been indicated in apoptosis, or death of cancer cells, in particular brain tumours and cells affected by leukaemia or colon cancer.

Dr Al Harrasi pointed out that the research was done under the chairmanship of Oman Medicinal Plants and Marine Natural Products at the Nizwa University and was funded jointly by the Oman Research Council and Nizwa University,

This discovery, the Nizwa University scientist says, will play a vital medicinal as well as economic role. “AKBA is very costly,” he said, explaining the economic benefits to the country.

Omani media have claimed that a “cure” for cancer had been found, which Al Harrasi denies.

“We would like to dispel certain misgivings regarding our discovery,” Dr Al Harrasi told Gulf News over the phone from Nizwa, about 160km northwest of Muscat.

“We have not discovered a breast cancer cure and it is not from oil as reported in some media and being circulated on WhatsApp as well as social media,” he added

The Assistant Dean for Scientific Studies and Research in Nizwa University also clarified that the compound had not been tested on humans. “We experimented on various cancer cell alliances for our research,” he clarified, adding that their experiments on several cancer cells showed positive results.

He also revealed that patent registration process was under process and 60 to 70 per cent of work was done. “The draft [for patent] has been accepted,” he said



http://ecancer.org/news/465.php

Frankincense oil derived from Boswellia carteri induces bladder tumor cell specific cytotoxicity

18 Mar 2009

Frankincense oil - a potential treatment option for bladder cancer

An enriched extract of the Somalian Frankincense herb Boswellia carteri has been shown to kill off bladder cancer cells. Frankincense oil is prepared from aromatic hardened gum resins obtained by tapping Boswellia trees. One of the main components of frankincense oil is boswellic acid, a component known to have anti-neoplastic properties. Research presented in the peer reviewed journal, BMC Complementary and Alternative Medicine found that  Frankincense oil might represent an alternative intravesical agent for bladder cancer treatment.

HK Lin and his team, from the University of Oklahoma Health Sciences Center and Oklahoma City VA Medical Center, set out to evaluate frankincense oil for its anti-tumour activity in bladder cancer cells. The authors investigated the effects of the oil in two different types of cells in culture: human bladder cancer cells and normal bladder cells. The team found that frankincense oil is able to discriminate between normal and cancerous bladder cells in culture, and specifically kill cancer cells.

Within a range of concentration, frankincense oil suppressed cell viability in bladder transitional carcinoma J82 cells but not in UROtsa cells. Comprehensive gene expression analysis confirmed that frankincense oil activates genes that are responsible for cell cycle arrest, cell growth suppression, and apoptosis in J82 cells. However, frankincense oil-induced cell death in J82 cells did not result in DNA fragmentation, a hallmark of apoptosis.

Article: Frankincense oil derived from Boswellia carteri induces tumor cell specific cytotoxicity
Mark Barton Frank, Qing Yang, Jeanette Osban, Joseph T Azzarello, Marcia R Saban, Ricardo Saban, Richard A Ashley, Jan C Welter, Kar-Ming Fung and Hsueh-Kung Lin http://www.biomedcentral.com/bmccomplementalternmed/



VIDEO

http://www.youtube.com/watch?v=hsJg_kmvQDE?
FRANKINCENSE FOR CANCER - PRE CLINICAL RESULTS

http://qwww.kfor.com/2013/04/30/the-biblical-cure/

Frankincense: The Biblical cure? | KFOR.com



PATENTS

Novel Salts Of Boswellic Acids And Selectively Enriched Boswellic Acids And Processes For The Same
US2013116211

New salts or ion-pair complexes obtained by a reaction between boswellic acids or selectively enriched 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) or 11-keto-beta-boswellic acid (KBA) compounds obtained through a new improved process, and an organic amine, more particularly with glucosamine. These salts or ion pair complexes are useful in nutraceuticals and in food supplements for anti-inflammatory and analgesic treatment of joints and cancer prevention or cancer therapeutic agents. These salts or ion pair complexes could also be used in cosmetic or pharmaceutical composition for external treatment of body parts or organs to treat inflammatory diseases or cancer.

[0001] This invention relates to novel salts or ion pair complexes of substituted/unsubstituted boswellic acid with certain organic bases particularly though not exclusively with glucosamine. This invention also includes an improved process for selectively enriching 3-O-acetyl-11-keto-[beta]-boswellic acid and 11-keto-[beta]-boswellic acid hereinafter referred as (AKBA) and (KBA) respectively from an extract containing a mixture of boswellic acids.

BACKGROUND ART

[0002] Inflammation is a critical protective biological process triggered by irritation, injury or infection, characterized by redness and heat, swelling, loss of function and pain. In addition to the foregoing induced conditions, inflammation can also occur due to age related factors. Life expectancy of general population has increased dramatically during the past few decades due to efficient control of infectious diseases and better access to nutritious food. This positive enhancement in life span coupled with changing environmental conditions elevated the incidence of chronic age-related diseases such as arthritis, diabetes, cancer, cardiovascular diseases, etc. Chronic inflammatory condition and cancer have become emerging health concerns in a number of countries across the globe and for people among all cultures. Arthritis is one of the most debilitating diseases of modem times. The quality of life for sufferers of these two diseases and their families is severely affected. Non-steroidal anti-inflammatory drugs are most commonly used remedies for rheumatic diseases. Presently, there has been a tremendous surge in demand for natural non-steroidal anti-inflammatory drugs (NSAIDs) because of their established safety and efficacy, through decades of usage by various cultures.

[0003] The inflammatory and carcinogenesis processes are known to be triggered by increased metabolic activity of arachidonic acid. Arachidonic acid diverges down into two main pathways during this process, the cyclooxygenase (COX) and lipoxygenase (LOX) pathways. The COX pathways lead to prostaglandin and thromboxane production and the LOX pathways leads to leukotrienes (LTS) and hydroxyl eicosatetetraenoic acid (HETEs). These classes of inflammatory molecules exert profound biological effects, which enhance the development and progression of human cancers,

[0004] Leukotrienes and 5(S)-HETE are important mediators for inflammatory, allergic and obstructive process. Leukotrienes increase micro vascular permeability and are potent chemotactic agents. Inhibition of 5-lipoxygenase indirectly reduces the expression of TNF-[alpha] (a cytokine that plays a key role in inflammation). 5-Lipoxygenase is therefore the target enzyme for identifying inhibitors, which have potential to cope with a variety of inflammations and hypersensitivity-based human diseases including asthma, arthritis, bowel diseases such as ulcerative colitis and circulatory disorders such as shock and ischaemia.

[0005] Similarly prostaglandins are intercellular messengers that are produced in high concentration at the sites of chronic inflammation and are capable of causing vasodilation, increased vascular permeability and sensitizing pain receptors. The pro-inflammatory prostaglandins (PGE2) are produced by inducible isoform cyclooxygenase-2 (COX-2). The prostaglandins that are important in gastrointestinal and renal function are produced by the constitutively expressed isoform, cyclooxygenase-1 (COX-1). COX-1 is the protective housekeeper isoform and it regulates mucosal cell production of mucous that provides a barrier between the acid and pepsin present in gastric secretions. Non-selective COX inhibitors thus produce serious side effects. Scientists around the world are thus investing a major effort in identifying non-steroidal anti-inflammatory drugs that inhibit 5-lipoxygenase and cyclooxygenase-2 enzymes. As both COX-2 and 5-LOX are commonly expressed in any kind of inflammatory condition, efforts are currently being focused to obtain the so called dual acting anti-inflammatory drugs that are able to inhibit both COX-2 and 5-LOX enzymes. Unfortunately, the odds of finding a new dual acting natural NSAID that can truly alleviate the symptoms of inflammatory diseases are very thin. Hence, the researchers conceived the idea that using a combination of drugs, one having the COX-2 inhibitory activity and the other having 5-LOX inhibitory activity, as the next best option.

[0006] Rheumatoid arthritis is a chronic inflammatory condition that affects the lubricating mechanism and cushioning of joints. As a result of this autoimmune disease the bone surfaces are destroyed, which leads to stiffness, swelling, fatigue and crippling pain. Osteoarthritis is the common form of arthritis and results primarily from progressive degeneration of cartilage glycoaminoglycons. The damage is often compounded by a diminished ability to restore and repair joint structures including cartilage. The smooth surface of the cartilage becomes hard and rough creating friction. As a result of this the joint gets deformed, painful and stiff. Studies have indicated that over 40 million Americans have osteoarthritis, including 80% of persons over the age of 50. The major focus for osteoarthritis treatment, should therefore involve agents that not only stimulate the production of biological substances necessary for regeneration of cartilage cells and proper joint function but also diminish pain inflammation.

[0007] It is therefore an object of the present invention to provide a salt or ion pair complex as a dietary supplement, that exhibits anti-arthritic properties without deleterious side effects.

[0008] Boswellic Acids

[0009] Gum resin of Boswellia species known as Indian frankincense has been used as an anti-inflammatory agent in Traditional Ayurvedic Medicine in India. Ancient Ayurvedic texts described its therapeutic use. Clinical trails performed by CSIR laboratories in India have shown fair to excellent results in 88% of the patients, with no adverse side effects (Singh, G. B., Status report, anti-inflammatory drugs from plant sources, 1982). A randomized, double blind, placebo controlled clinical trials on patients with osteo-arthritis of knee exhibited statistically significant improvement in the pain, decreased swelling and increased knee flexion etc. (Kimmatkar, Phytomedicine, 2003, 10, 3-7), The therapeutic effects shown by Boswellia serrata extract were comparable to those exhibited by sulfasalazine and mesalazine in patients with ulcerative colitis. (Gupta, I., et al., Eur. J. Med. Res., 1998, 3, 511-14 and Gerhardt, H., et. al., Gastroenterol., 2001, 39, 11-17). The source of anti-inflammatory actions has been attributed to boswellic acids (Safayhi, H., et al., Planta Medica, 1997, 63, 487-493 and J. Pharmacol. Exp. Ther., 1992, 261, 1143-46, both the journals published from USA), a group of triterpene acids isolated from the Boswellia resin (Pardhy, R. S., et al., Indian J. Chem., 1978, 16B, 176-178). These compounds exert anti-inflammatory activity by inhibiting 5-lipoxygenase (5-LOX). The boswellic acids also gained prominence recently for their antiproliferative actions. Boswellic acids inhibited several leukemia cell lines in vitro and inhibited melanoma growth and induced apoptosis (Hostanska, K., et al., Anticancer Res., 2002, 22(5), 2853 -62). The acetyl boswellic acids were found to be unique class of dual inhibitors of human topoisomerases I and II a (Syrovets, T. et al., Mol. Pharmacol., 2000, 58(1), 71-81). Immunomodulatory activity of boswellic acids had been reported by Sharma et al. in Phytotheraphy Research, 1996, 10, 107-112, published from USA. A detailed study on the structural requirements for boswellic acids indicated that of all the six acids, 3-O-acetyl-11-keto-[beta]-boswellic acid, hereinafter referenced as AKBA shows most pronounced inhibitory activity against 5-LOX (Sailer, E. R., et al., British J. Pharmacology, 1996, 117, 615-618). AKBA acts by unique mechanism, in which it binds to 5-LOX in a calcium-dependent and reversible manner and acts as a non-redox-type, non-competitive inhibitor (Sailer, E. R., et al., Eur. J. Biochem., 1998, 256, 364-368). The AKBA or a plant extract or composition containing it was reported to be effective for topical application, as an agent to soften lines and/or relax the skin (Alain, M., et. al., U.S. patent application No. 2004/0166178, dated Aug. 26, 2004). AKBA has thus become the subject of intensive research for its potential for the treatment of chronic inflammatory disorders.

[0010] Glucosamine

[0011] Glucosamine is a natural substance found in high quantities in joint structures. The main function of glucosamine in joint structures is to produce cartilage components necessary for maintaining and repair joint tissue. Glucosamine stimulates the formation of joint structural components such as collagen, the protein of the fibrous substances that holds the joints together and helps to build-up the cartilage matrix, Collagen is the main component of the shock-absorbing cushion called articular cartilage. It is also a necessary nutrient in the production of synovial fluid. Some people may lose the ability with age to produce glucosamine, thereby inhibiting the grpwth of cartilage destroyed during wear and tear in osteoarthritis patients (Towheed, T. E., Arthritis and Rheumatism, 2003, 49, 601-604). When taken orally as a dietary supplement in the form of glucosamine sulfate, it has been shown to exert protective effect against joint destruction and is selectively used by joint tissues to promote healthy joint function and show potential therapeutic effect in osteoarthritis (Perry, G. H., et al., Ann. Rheum. Dis., 1972, 31, 440-448).

[0012] Several double-blind studies with glucosamine sulfate showed therapeutic effects comparable to or even better than non steroidal anti-inflammatory drugs in relieving the symptoms of osteoarthritis (Vaz, A. L., Curr. Med, Res. Opin., 1982, 8, 145-149; D'Ambrosia, E. D., et al., Pharmatherapeutica, 1982, 2, 504-508 and Tapadinhas, M. J., et al., Pharmatherapeutica, 1982, 3, 157-168). The NSAIDs offer only symptomatic relief, whereas glucosamine addresses the root cause of osteoarthritis disease. It support body's natural ability to tackle the disease on its own by providing the building blocks to many structural components such as glucosaminoglycons to repair the damage caused by osteoarthritis. Glucosamine hydrochloride is used for this study.

DISCLOSURE OF THE INVENTION

[0013] The organic solvent extract of the gum resin of Boswellia serrata contain a total of six boswellic acids and two timcallic acids. These acids are shown in FIG. 1, and are represented by B1, B2, B3, B4, B5, B6, T1, T2 and T3. Studies have indicated AKBA as the most potent an anti-inflammatory agent among all the boswellic acids. The concentration of AKBA, indicated as B2 in the FIG. 1, amounts only in the range of 1-10% in the extract, but most often it is in the range of 2-3%. The potential usefulness of boswellic acids in general and AKBA in particular can be a great incentive to take-up further development of these compounds in all possible aspects.

[0014] The present invention is aimed at selective enrichment of active compounds, KBA and AKBA to a therapeutically useful range such as 30% to 100% from natural Boswellia extract using a new improved process and then converting the enriched compounds to a salt or ion pair complex with enhanced solubility and improved therapeutic efficacy for use as an anti-arthritic dietary supplement. The salt or ion pair combination may be accomplished by using an acid function of the boswellic acid and an amine function from amino organic compounds, especially glucosamine.

[0015] The enrichment of AKBA from natural Boswellia extract was already described in international patent application (PCT #WO 03/074063, dated. 12th September 2003) and also in US patents (application #20030199581, publication dated 23 Oct. 2003 and application #20040073060, publication dated 15 Apr. 2004). The processes described in these patents involve multi-step procedures and requires tedious work-up and chromatographic purifications. The present invention is an improved method, where in the acetylation and allylic oxidation steps are conducted in a single pot. This process eliminates the need for labor-intensive work-up following acetylation and time consuming product drying before proceeding to the oxidation step, as required by the processes reported in the patents and journal articles. This process also efficiently utilizes the un-reacted pyridine and acetic anhydride from the acetylation step to form highly active oxidizing systems such as CrO3/pyridine and CrO3/acetic anhydride. The present invention effectively reduces the overall reaction time for peracetylation and the oxidation steps. The new process eliminates the presence of possible chromium impurities in the KBA/AKBA enriched (30-40%) product by acid/base treatment without any need for chromatography.

[0016] A fraction enriched to 30-40% 11-keto-[beta]-boswellic acid (KBA), can be accomplished by subjecting the crude mixture to basic treatment, followed by filtration and acidification of the mother liquor, and then separation of the white solid by filtration and drying, It was then reacetylated to obtain 30-40% AKBA enriched fraction, The fractions enriched to higher percentage (40-100%) of KBA and AKBA can be obtained by applying chromatographic methodology on hydrolysis mixture and re-acetylation mixture, respectively.

[0017] An ionic salt or ion pair complex of boswellic acids containing AKBA in the range of 5 to 100% can be obtained by using appropriately enhanced boswellic compound and a suitable amine compound and adopting the representative procedure given in the examples.

[0018] This invention relates to novel salts or ion pair complexes of boswellic acid and keto boswellic acid and acetyl keto boswellic acid with glucosamine having the following general formula.

wherein R1 and R2 are H or taken together to form a keto group;
R3 is H or acyl group;
X is an heterocyclic base or an organic bases represented by NHR4R5R6:
wherein R4, R5 and R6, are H or substituted or unsubtituted lower or higher
alkyl group or aryl group or cyclic alkyl group.

[0024] Wherein the organic bases are glucosamine (2-amino-2-deoxy-D-glucose), nicotinamide (3-pyridinecarboxamide), pyridoxins (5-hydroxy-6-methyl-3,4-pyridinedimethanol), caffeine (3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dxone), creatine (N-(aminoiminomethyl)-N-methylglycine), allantoin (2,5-dioxo-4-imidazolidinyl)urea), Theobromine (3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione), theophylline (3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione), mesalamine (5-amino-2-hydroxybenzoic acid), enfenamic acid (2-[(2-phenylethyl)amino]benzoic acid), etofenamate (2-[[3-(trifluoromethyl)phenyl]-amino]benzoic acid 2-(2-hydroxyethoxyethyl ester), flufenamic acid (2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid), meclofenamic acid (2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid), mefenamic acid (2-[(2,3-dimethylphenyl)-amino]benzoic acid), niflumic acid (2-[[3-(trifluoromethyl)phenyl]-amino]-3-pyridinecarboxylic acid), talniflumate (2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid 1,3-dihydro-3-oxo-1-isobenzofuranyl ester), terofenamate (2-[(2,6-dichloro-3-methylphenyl)-amino]benzoic acid ethoxymethyl ester), tolfenamic acid (2-[(3-chloro-2-methylphenyl)-amino]benzoic acid), S-adenosylmethionine ((3S)-5'-[(3-amino-3-carboxypropyl)methylsulfonio]-5'-deoxyadenosine inner salt), 3-amino-4-hydroxybutyric acid, amixetrine (1[2-(3-methylbutoxy)-2-phenylethyl]pyrrolidine), benzydamine (N,N-dimethyl-3-[[1-(phenylmethyl)-1H-indazol-3-yl]oxy]-1-propanamine), difenpiramide (N-2-pyridinyl-[1,1'-biphenyl]-4-acetamide), ditazol (2,2'-[(4,5-diphenyl-2-oxazolyl)imino]-bisethanol), emorfazone (4-ethoxy-2-methyl-5-(4-morpholinyl)-3(2H)-pyridazinone), fepradinol ((+-)-[alpha]-[[(2-hydroxy-1, 1-dimethylethyl)-amino]methyl]benzeneniethanol), paranyline (4-(9H-fluoren-9-ylidenemethyl)benzene-carboximidamide), perisoxal ([alpha]-(5-phenyl-3-isoxazolyl)-1-piperidineethanol).

[0025] We have disclosed a simple method by which salts or ion-pair complexes of boswellic acids with hetero-atom bases (also referred to as 'organic base') can be made for their inclusion in dietary or pharmaceutical compositions that provide reduction in inflammation and other health benefits. These salts or ion pair complexes are made by simple acid-base reaction, as shown in eq, 1, between an organic acid (RCOOH) and an organic base (NR4R5R6).

RCOOH+NR4R5R6->RCOO<-+>NHR4R5R6 (equation 1)

[0026] The new composition according to this invention may be prepared by the following processes:

(a) By reacting boswellic acids or ketoboswellic acid or acetyl ketoboswellic acid with organic base.
(b) By in situ generation of organic free base and reacting with boswellic acids or ketoboswellic acid or acetyl ketoboswellic acid.

[0029] In the first process, stoichiometric equivalents of the reactants are mixed to obtain the desired salts or ion pair complexes. Preferably, the reaction is initiated by the slow addition of organic free base, particularly, glucosamine free base to an aqueous methanolic solution of boswellic acids. Boswellic acids (48% by HPLC) may be obtained by a known process of extraction from the gum resin of Boswellia serrata. Glucosamine free base may be liberated from glucosamine hydrochloride by anionic exchange resin treatment. The enriched 11-ketoboswellic acid or 3-O-acetyl-11-ketoboswellic acid (30%-100%) was obtained from the gum-resin of Boswellia serrata using an improved method described herein.

[0030] The salts or pair complexes prepared by this process may contain between 10 to 70% of boswellic acids. 5-40% of glucosamine.

[0031] According to the second process of preparing the compounds of this invention, stoichiometric quantities of boswellic acids, potassium hydroxide and organic base salts, particularly, glucosamine hydrochloride are reacted in aqueous methanol medium.

[0032] A further aspect of the present invention is a pharmaceutical formulation comprising a compound as described above in a pharmaceutically acceptable carrier (e.g., an aqueous or a non aqueous carrier).

[0033] A still further aspect of the present invention is a method of treating inflammatory diseases, comprising administering to a human or animal subject in need thereof a treatment effective amount (e.g., an amount effective to treat, slow the progression of, etc.) of a compound as described above.

[0034] Preferred embodiments relating to the improved process of enriching AKBA in natural Boswellia extract and making the salts or ion pair complexes are presented in examples 1 to 6.

[0035] Though the following examples describe a specific embodiment of this invention, obvious equivalents and modifications known to persons skilled in the art are not excluded from the scope of the appended claims.

EXAMPLE 1

Isolation of 11-keto-[beta]-boswellic acid and 3-O-acetyl-11-keto-[beta]-boswellic acid

[0036] 1a). Single Pot Conversion of Boswellia Extract into AKBA Enriched Fraction:

[0037] To a solution of Boswellia serrata extract (85%, 10 kg,) in pyridine (5.4 L), in a 100 L all glass reactor equipped with a water-cooled reflux condenser, was added acetic anhydride (4.2 L) at room temperature and the mixture was subjected to heating at 60-65[deg.] C. under stirring. After 3 h, the mixture was cooled to ambient temperature and diluted with acetic acid (24 L) and acetic anhydride (24 L). The contents were cooled and treated slowly with chromium trioxide (6.4 kg) while maintaining the temperature under 40[deg.] C. The stirring was continued for another 2 h after the addition, and then the mixture was poured into ice water and the contents were mixed thoroughly. The solid was filtered, washed with water and dried in a vacuum oven to obtain a residue (14 kg). The HPLC analysis of the crude product showed complete conversion of boswellic acids B1, B4 and B6 to B2 (AKBA).

[0038] 1b). Isolation of 30-40% 3-O-acetyl-11-keto-[beta]-boswellic acid: The above crude reaction mixture (5 kg) was added to 4N hydrochloric acid (45 L) and heated at 60[deg.] C. for 4 h. The mixture was cooled to ambient temperature and filtered. The precipitate was washed with 4N HCl, followed by water and dried in a vacuum oven to obtain AKBA enriched to 30-40% (2.8 kg).

[0039] 1c). Isolation of 3-O-acetyl-11-keto-[beta]-boswellic acid: The above, enriched compound (500 g) was subjected to silica column chromatography using 5% to 30% ethyl acetate/hexane mixtures. The fractions were monitored by TLC and those containing AKBA (30%-60%) were combined and subjected crystallization in hexane and ethyl acetate mixtures to obtain fractions enriched up to 85% AKBA, Repeated crystallization in the same solvent system yielded AKBA enriched up to 100%.

[0040] 1d). Isolation of 11-keto-[beta]-bowellic acid: Alternatively, the crude mixture was dissolved in methanol and subjected to base treatment (8N KOH), The precipitate was separated by filtration and discarded. The mother liquor was acidified and the off-white precipitate was filtered, washed with water and dried under vacuum to obtain 30-40% ketoboswellic acid (KBA). The 11-keto-[beta]-boswellic acid mixture (200 g) obtained was adsorbed on 250 g of silica gel and subjected column chromatography over 500 g of silica. The column was eluted with hexane, 10% ethyl acetate/hexane, 20% ethyl acetate/hexane and 30% ethyl acetate/hexane mixtures. The fractions were monitored by TLC and the fractions containing 11-keto-p-boswellic acid were combined and evaporated and the residue was subjected to repeated crystallization from ethyl/hexane mixtures to obtain pure 11-keto-[beta]-boswellic acid (45 g, 95-100%. purity).

[0041] 1e). In a further variation of the process mentioned in example 1a, the addition of acetic anhydride was eliminated. Instead the peracetylated mixture was diluted with 20 L of acetic acid and treated with CrO3 (6.4 kg) in 100 L of acetic acid. The reaction mixture was quenched with excess water after 24 h, and processed as described in example 1a,

EXAMPLE 2

[0042] Glucosamine salt of boswellic acids; To a solution of boswellic acids (2 g, 48% boswellic acids) in 95% aqueous methanol (50 mL) was added glucosamine free base solution (8.6 mL, 0.4 g) and stirred at rt for 1 h. Then the solvent was evaporated under reduced pressure and dried to give glucosamine salt or ion pair complex of boswellic acids as gray colour powder (2.3 g), pH, 6,3, soluble in 90% aqueous methanol.

[0043] The analytical characteristics of the glucosamine salt or ion pair complex of boswellic acids thus obtained are, B1, 4.75%, B2, 2,10%, B3, 5.44%, B4, 14.91%, B5, 2.18%, B6, 8.66%; total: 38.04%; glucosamine (as free base) is 8.52%.

EXAMPLE 3

[0044] Glucosamine salt of boswellic acids (KCl): To a solution of boswellic acids (5 g, 48% boswellic acids) in methanol (125 mL) was added a solution of glucosamine hydrochloride (2 g) in water (8 mL) and stirred at rt for 15 min. Then potassium hydroxide (0.52 g, 20% aqueous solution, 2.6 mL) was charged slowly for 10 min and the solution was stirred at rt for 1 h. The solvent was evaporated under reduced pressure and dried to give glucosamine salt or ion pair complex of boswellic acids as gray colour powder (7.5 g), pH, 6.8, soluble in 90% aqueous methanol.

[0045] The analytical characteristics of the glucosamine salt or ion pair complex of boswellic acids thus obtained are, B1, 4.04%, B2, 1.86%, B3, 4.65%, B4, 12.73%, B5, 1.76%, B6, 7.34%; total: 32.38%; glucosamine (as free base) is 12.44%.

EXAMPLE 4

[0046] Glucosamine salt of boswellic acids (KCl): To a solution of boswellic acids (5 g, 48% boswellic acids) in methanol (125 mL) was added a solution of glucosamine hydrochloride (4g) in water (11 mL) and stirred at rt for 15 min. Then potassium hydroxide (0.52 g, 20% aqueous solution, 2.6 mL) was charged slowly for 10 min and the solution was stirred at rt for 1 h. The solvent was evaporated under reduced pressure and dried to give glucosamine salt or ion pair complex of boswellic acids as gray colour powder (9.6 g), pH, 6.6, soluble in 90% aqueous methanol.

[0047] The analytical characteristics of the glucosamine salt or ion pair complex of boswellic acids thus obtained are, B1, 3.14%, B2, 1.37%, B3, 3.36%, B4, 9.75%, B5, 0.93%, B6, 4.76%; total: 23.31%; glucosamine (as free base) is 27.16%.

EXAMPLE 5

[0048] Glucosamine salt of Acetyl ketoboswellic acid (KCl); To a solution of acetyl ketoboswellic acid (5 g, 30% AKBA) in methanol (100 mL) was added a solution of glucosamine hydrochloride (0.63 g) in water (3 mL) and stirred at rt for 15 min. Then potassium hydroxide (0.164 g, 20% aqueous solution, 0,82 mL) was charged slowly for 10 min and the solution was stirred at rt for 1 h. The solvent was evaporated under reduced pressure and dried to give glucosamine salt or ion pair complex of acetyl ketoboswellic acid as gray colour powder (4.8 g), pH, 6.7, soluble in 90% aqueous methanol.

[0049] The analytical characteristics of the glucosamine salt or ion pair complex of acetyl ketoboswellic acid thus obtained are, AKBA is 27.68%; glucosamine (as free base) is 5.42%.

EXAMPLE 6

[0050] Glucosamine salt of Acetyl ketoboswellic acid (KCl): To a solution of acetyl ketoboswellic acid (5 g, 30% AKBA) in methanol (100 mL) was added a solution of glucosamine hydrochloride (5 g) in water (15 mL) and stirred at rt for 15 min. Then potassium hydroxide (0.2 g, 20% aqueous solution, 1.0 mL) was charged slowly for 10 min and the solution was stirred at rt for 1 h. The solvent was evaporated under reduced pressure and dried to give glucosamine salt or ion complex of acetyl ketoboswellic acid as gray colour powder (9.3 g), pH, 5.6, soluble in 90% aqueous methanol.

[0051] The analytical characteristics of the glucosamine salt or ion pair complex of acetyl ketoboswellic acid thus obtained are, AKBA is 15.30%; glucosamine (as free base) is 39.44%.



Novel anti-cancer purely natural medicine (11-carbonyl-beta-acetyl boswellic acid)
CN101724005

The invention relates to a novel broad spectrum purely natural medicine that can specifically inhibit phosphorylation of protein T-kappa-B to prevent nuclear transport of T-kappa-B so as to inhibit the growth of cancer cell, thereby treating cancer. The novel medicine is a natural extractive, and has the advantages of low production cost, high curative effect and less side effect.



COMPOSITIONS AND METHODS FOR TREATING AND PREVENTING INFLAMMATORY AND/OR DEGENERATIVE PROCESSES IN HUMANS AND OTHER ANIMALS
WO2007011674  

Disclosed are compositions useful for treating Alzheimer's disease, atherosclerosis, arteriosclerosis, osteoarthritis and other degenerative joint diseases, Huntington's chorea, Parkinson's disease, optic atrophy, retinitis pigmentosa, macular degeneration, muscular dystrophy, aging-associated degenerative processes, asthma, dermatitis, laminitis, pemphigoid, pemphigus, reactive airway disease (e.g., COPD, IAD), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) , multiple sclerosis, rheumatoid arthritis, periodontal disease, systemic lupus erythematosus, sarcoidosis, psoriasis, type I diabetes, ischemia-reperfusion injury, chronic inflammatory diseases, geriatric wasting, cancer cachexia, cachexia associated with chronic inflammation, sick feeling syndrome, and other inflammatory and/or degenerative diseases, disorders, conditions,; and processes in humans and other animals. In one embodiment, the compositions include at least 4 of the following: a MMPl inhibitor, a MMP2 inhibitor, a MMP3 inhibitor, a MMP7 inhibitor, a MMP9 inhibitor, an ADAMTS-4 inhibitor, a MMP13 inhibitor, and a MMP14 inhibitor. In another embodiment, the compositions include a curcuminoid, a polymethoxylated flavone, a catechin, and a boswellic acid.



WATER SOLUBLE BOSWELLIC ACIDS, THEIR PREPARATION AND USE FOR TREATING IMFLAMMATORY CONDITION    
WO02066491

A new composition which can be formed through a method comprising: (a) dissolving mixtures of boswellic acids in a water and alcohol solution to form a mixture; (b) adding one or more alkali salts to the mixture to form a salt solution; (c) filtering the solution to separate un-reacted alkali salt from a filtrate; and (d) recovering the soluble boswellic acid mixture from the filtrate. Additionally, the new composition can be formed by using super critical carbon dioxide. The new composition can be used to alleviate numerous inflammatory conditions, including, but not limited to, rheumatoid arthritis and osteoarthritis, colon cancer, prostate cancer and breast cancer, and a broad range of neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease. The composition can be administered parenterally, orally, or topically.

BACKGROUND OF THE INVENTION :

[0003] Boswellia serrata is a large, branching, deciduous tree, which grows abundantly in the dry, hilly parts of India. The gum resin exudate of this tree, known in the vernacular as"Salai guggal", has been used in the Ayurvedic system of medicine for the management of arthritis, respiratory diseases, and liver disorders.

The major use of Boswellia serrata in modern medicine is as an anti-arthritic and anti-inflammatory pharmacological agent.

[0004] The active principles found in the gum resin, specifically a combination of boswellic acids, have emerged as effective non-steroidal anti-inflammatory compounds (NSAID's) with broad biological activities and also a low ulcerogenic index. Compared experimentally with the anti-inflammatory drug phenylbutazone, boswellic acids did not produce injury to the gastrointestinal mucosa. The most popular NSAID, aspirin, although much better tolerated than its parent compound salicylates, still has serious side effects, e. g. gastrointestinal irritation and bleeding which limit its long-term use. In addition, aspirin is contraindicated in patients who have experienced asthma, urticaria (in general allergic reactions), and should be administered with caution in children and teenagers due to the risk of Reye syndrome.

[00005] One way in which to explain how boswellic acids function as NSAIDs in the treatment of inflammatory conditions is to compare these natural compounds to aspirin without the typical gastrointestinal irritation. Similar to aspirin, boswellic acids inhibit the pathway leading from arachidonic acid (a derivative of our body's phospholipids) to its metabolic derivatives called leukotrienes and prostaglandins.

An excess of leukotrienes and prostaglandins may be responsible, directly or indirectly, for the classic signs of inflammation ; redness (due to dilated vessels), swelling (due to the blood vessels leaking out), pain (due to activation of the pain receptors) and increased heat over the affected part of the body. The specific biochemical mechanism of boswellic acids differs from that of aspirin, however both compounds result in the diminishment of the mediators of inflammation, leukotrienes or prostaglandins, and the inflammation is subdued.

[0006] Studies designed to determine the anti-inflammatory mechanism of boswellic acids indicate that their primary mode of action involves the inhibition of 5lipoxygenase, the key enzyme responsible in the formation of leukotrienes.

Additionally, boswellic acids do not appear to impair the peroxidation of arachidonic acid by iron and ascorbate. These results suggest that boswellic acids are safe, specific, non-redox inhibitors of leukotriene synthesis that operate through a well defined mechanism.

[0007] One of the most interesting properties of boswellic acids is their anticomplementary activity. In in vitro experiments boswellic acids prevented a wellknown inflammatory"chain-reaction"involving several protein compounds collectively known as"complement". This is due to the inhibition of an enzyme that activates one of the components of complement, C3 convertase. The domino effect of the complement in the course of rheumatoid arthritis (or a similar chronic inflammatory process) leads to a subsequent elevation of the enzymes (e. g. cathepsins, glucuronidase and human leukocyte elastase (HLE)) causing excessive catabolism (wasting) of the joint-forming glycoproteins and glycosaminoglycans.

This tissue destructive process leads to continuously worsening joint disfigurement, pain, and limited mobility. As a consequence of complement-mediated tissue destruction, there is an increased release of markers (metabolites) of the connective tissue, e. g. hydroxyproline, hexosamine and uronic acid. Boswellic acids have been found to decrease the levels of tissue destructive enzymes and also of the levels of urinary hydroxyproline, hexosamine and uronic acid in the acute and chronic phases of experimental arthritis.

[0008] There are four major b-boswellic acids involved in the inhibition of 5lipoxygenase and related anti-inflammatory events. These are: b-Boswellic Acid (BBA), Acetyl-b-Boswellic Acid (ABBA), 11-keto-b-Boswellic Acid (KBBA), Acetyl-11- keto-b-Boswellic (AKBBA), listed here in the order of increasing anti-inflammatory properties.

[0009] Boswellic acids have been found to be effective in alleviation of numerous inflammatory conditions, including, rheumatoid arthritis and osteoarthritis.

[0010] A standardized extract of boswellic acids (200 mg tid) was evaluated in a four week double blind, cross-over trial in 30 patients suffering from rheumatoid arthritis. The mean arthritic score (sum of symptoms) and the biochemical index of inflammation in the group receiving boswellic acids came down significantly after the treatment. However, when the placebo was substituted (crossover), the subjective and objective indices of arthritis rose again. (See Majeed, M, Badmaev, V, Gopinathan, S, Rajendran, R, Norton, T. Boswellin The Anti-inflammatory Phytonutrient. Nutriscience Publishers, Inc. Piscataway, N. J. 1996. pp. 78.) [0011] In another 20 patient, double blind, crossover study a boswellia gum resin extract (200 mg tid) combined in an herbomineral formula was evaluated in the treatment of rheumatoid arthritis and separately in osteoarthritis. Active and placebo treatments were given for a period of three months. After a washout period of two weeks, the regimens were crossed-over. The three month active therapy resulted in a significant decrease in severity of pain, morning stiffness, improved joint mobility score, grip strength score and the overall disability score compared to the placebo group. The biochemical index of inflammation was also significantly improved due to the treatment. (See Kulkarni, RR, Patki, PS, Jog, VP, Patwardhan, G & B. Efficacy Of An Ayurvedic Formulation In Rheumatoid Arthritis: A Double-Blind, Placebo Controlled, Cross-Over Study. Ind J Pharmacol. 1992 ; 24: 98-101.) [0012] Ulcerative colitis is an example of a chronic inflammatory process in the bowel, which may be caused and/or aggravated by excessive leukotriene production.

Effects of Boswellia serrata gum resin (350 mg thrice daily for 6 weeks) vs. the NSAID sulfasalazine was studied in patients with ulcerative colitis. The tested parameters, including stool properties, istolopathology of rectal biopsies, and blood biochemistry improved after treatment with the gum resin. As a result of the treatment, 82% of patients went into remission, as compared to a 75% remission rate obtained with sulfasalazine. (See Gupta, 1, Parihar, A, Malhotra, P, Singh, GB, Ludtke, R, Safayhi, H, Ammon, HP. Effects of Boswellia serrata gum resin in patients with ulcerative colitis. Eur J Med Res. 1997 Jan; 2 (1) : 37-43.) [0013] Boswellic acids were also tested in the management of asthma, since a new generation of anti-asthmatic drugs is based on the premise of being leukotriene inhibitors. In a double blind, placebo-controlled study 40 patients with a several years'history of bronchial asthma were treated with 300 mg tid of boswellia gum resin for a period of six weeks. Seventy percent of the patients responded to the treatment as evidenced by a reduction in dyspnea, ronchi, and number of attacks, improvement in lung tests and blood biochemistry. Only 27% of the patients receiving placebo showed clinical improvement. (See Gupta, 1, Gupta, V, Parihar, A, Gupta, S, Ludtke, R, Safayhi, H, Ammon, HP. Effects Of Boswellia Serrata Gum Resin In Patients With Bronchial Asthma: Results Of A Double-Blind, Placebo
Controlled, 6-Week Clinical Study. Eur J Med Res. 1998; 3: 511-514.) [0014] Finally, boswellic acids also have use in the veterinary field. Several veterinarians found success using boswellic acids in the treatment of chronic inflammatory conditions in horses such as stifle problems, sore backs, bowed tendons and bone spurs. In addition, a preliminary study of boswellic acids in aging pet dogs and cats showed beneficial effects in alleviating arthritic conditions. (See Majeed, M, Badmaev, V, Gopinathan, S, Rajendran, R, Norton, T. Boswellin The
Anti-inflammatory Phytonutrient. Nutriscience Publishers, Inc. Piscataway, N. J. 1996. pp. 78.) [0015] Sabinsa Corporation manufactures different grades of Boswellic acids known under the trademark Boswellin@, two of these are Boswellin (standardized for 25% boswellic acids) and Boswellin Forte (standardized for 40% boswellic acids).

More specifically, the minimum amount of each boswellic acid that must be present in these grades is:
Boswellin Forte Boswellin BBA min. 11.0% 6.0% ABBA min. 8.0% 4.0% KBBA min. 7.0% 3.0% AKBBA min. 4.0% 1.5% [0016] Please note that, of course, every acid may not be present in its minimum amount as the required total percentages of boswellic acids (40% and 25%) would not be met if this occurred.

[0017] Such non-water soluble mixtures of BBA, ABBA, KBBA, and AKBBA boswellic acids can be used as a pharmaceutical. Since the ancient times, frankincense has been used in the preparation of cosmetics and perfumes, and also as a fixative in perfumes, soaps, creams, lotions and detergents. Frankincense is a common name for Boswellia gum resin, and Boswellia gum resin is a raw source from which boswellic acids are extracted. The stabilizing effect of frankincense in cosmetic preparations is directly related to the biological properties of boswellic acids. The anti-inflammatory properties of boswellic acids can also yield an interesting applications for topical and cosmetic use of the extract of Boswellia serrata. Boswellia cream for the management of inflammatory conditions has been available for several years in the US market. Its therapeutic composition includes, roughly 5 wt. % boswellic acids, 0.025 wt. % capsaicin, an extract of Capsicum annum fruits, and 10 wt. % methyl salicylate.

[0018] However, a problem associated with these formulations is that they are not soluble in water. Therefore, there is a great need in the field for water soluble boswellic acid mixtures and salts.

SUMMARY OF THE INVENTION :

[0019] The new water-soluble composition can be formed through a method comprising the steps of: (a) dissolving mixtures of boswellic acids in a water and alcohol solution to form a mixture; (b) adding one or more alkali salts to the mixture to form a salt solution; (c) filtering the solution to separate un-reacted alkali salt from a filtrate; and (d) recovering the soluble boswellic acid mixture from the filtrate.

[0020] Additionally, the new composition can be formed by using super critical carbon dioxide. The new composition can be used to alleviate numerous inflammatory conditions, including, but not limited to, rheumatoid arthritis and osteoarthritis, colon cancer, prostate cancer and breast cancer, and a broad range of neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease. It can also be used in the prevention and treatment of cardiovascular conditions such as stroke, coronary artery disease or thrombophlebitis. The composition can be administered parenterally, orally, or topically.

DETAILED DISCLOSURE :

[0021] As stated above, the composition can be formed by (a) dissolving mixtures of boswellic acids in a water and alcohol solution to form a mixture, (b) adding one or more alkali salts to the mixture to form a salt solution, (c) filtering the salt solution to separate un-reacted alkali salt from a filtrate, and (d) recovering the soluble boswellic acid mixture from the filtrate.

[0022] Preferably, though, the method involves (a) dissolving boswellin forte in a water and 5% methanol solution to form a mixture, (b) adding one or more potassium salts to the mixture to form a salt solution and then stirring the salt solution at room temperature, (c) filtering the solution with a nutsche filter to separate un-reacted potassium salts from a filtrate, (d) recovering the soluble boswellic acid mixture from the filtrate, (e) drying the filtrate with a vacuum drier at a temperature of no more than 50 C, and (f) powdering the filtrate.

[0023] More preferably, the filtrate can be dried through concentrating the filtrate free of the solvent to obtain a solid, wherein this step also further comprises dissolving the obtained solid in water to obtain a secondary mixture, charcoalizing the secondary mixture, filtering the charcoalized secondary mixture and spray-drying the resulting product.

[0024] Additionally, it is also possible to use the super critical carbon dioxide method of obtaining the boswellic acid mixture. Such a process would comprise the steps of (a) dissolving a mixture of boswellic acids, preferably boswellin forte, in a water and alcohol solution to form a mixture, (b) adding one or more alkali salts to the mixture to form a salt solution, (c) treating the salt solution with supercritical carbon dioxide, (d) allowing the supercritical carbon dioxide to evaporate to leave an oleoresin, (e) passing an alcohol solution of the oleoresin through a column packed with an anion exchange resin, and (f) collecting the soluble boswellic acid mixture from the eluent. Furthermore, it is preferred that the treatment of the salt solution take place for at least 10 hours and that the alcohol solution be 5% methanol and 95% water. Suitable resins include Amberjet 4200 (cl), Amberlite IRA 410, Amberlite IRA 900, Dowex 1x2-100, Dowex 22cl, Dowex Marathon A2, Dowex MSA 1, Dowex 550 A, all of which are Rohm-Haas or Dow products. The oleoresin is preferably passed through the resin at a rate of 20-50 L per hour.

[0025] The processes described above produce a water soluble composition, preferably comprising at least 12.5% by weight of the alkali salt of BBA, at least 9.57% by weight of the alkali salt of ABBA, at least 8.15% by weight of the alkali salt of KBBA, and at least 3.72% by weight of the alkali salt of AKBBA, the remainder of the water soluble composition being organic acids or matter, and the alkali salts thereof. This composition of boswellic acids is suitable for the treatment of many inflammatory conditions including rheumatoid arthritis and osteoarthritis, colon cancer, prostate cancer and breast cancer, and a broad range of neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease. It can also be used in the prevention and treatment of cardiovascular conditions such as stroke, coronary artery disease or thrombophlebitis.

[0026] The composition may be administered to the subject orally, parenterally, or topically. For preparing pharmaceutical compositions containing compounds of the invention, inert, pharmaceutical acceptable carriers are used. The pharmaceutical carrier can be either solid or liquid. Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, creams, and cachets.

[0027] A solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is generally a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0028] Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient. Suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter and the like. The pharmaceutical compositions can include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it. In a similar manner, cachets are also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

[0029] Liquid pharmaceutical compositions include, for example, solutions suitable for oral or parenteral administration, or suspensions, and emulsions suitable for oral administration. Sterile water solutions of the active component or sterile solutions of the active component in solvents comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.

[0030] Sterile solutions can be prepared by dissolving the active component in the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions.

[0031] Aqueous solutions for oral administration can be prepared by dissolving the active compound in water or other appropriate solvents and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art. Preferably, the pharmaceutical composition is in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the boswellic acid mixtures. The unit dosage form can be a-packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.

[0032] The specific dosages employed, however, can be varied depending upon the requirements of the patient, and the severity of the condition being treated. The preferred dosage of the alkali boswellic acid salts given is 50-800 mg per day. More preferably, the dosage is 100-600 mg per day. Even more preferred is a dosage of 150-300 mg per day. Most preferred is a dosage of about 200 mg per day, which is preferably administered by doses of 200 mg of the boswellic acid salt composition 3 times a day. The determination of optimum dosages for a particular situation is within the skill of the art.

BRIEF DESCRIPTION OF DRAWINGS :

[0033] Figure 1: This diagram reflects the boswellic acid composition of the Potassium Boswellin used in Example 1 and the composition of the Boswellin forte used to create the Potassium Boswellin used in Example 1.

[0034] Figure 2: This diagram reflects the presence of the four boswellic acids in the serum of Individual A at 5,10,20,40,80, and 160 minutes.

[0035] Figure 3: This diagram reflects the presence of the four boswellic acids in the serum of Individual B at 5,10,20,40,80, and 160 minutes [0036] Figure 4: This diagram is a graph charting the serum levels of the various four boswellic acids in the serum of Individual A at the 5,10,20,40,80, and 160 minute intervals.

[0037] Figure 5: This diagram is a graph charting the serum levels of the various four boswellic acids in the serum of Individual B at the 5,10,20,40,80, and 160 minute intervals

EXAMPLES
Example 1:

An initial batch of 1 kg Potassium Boswellin was prepared using 40% Boswellin Forte material (see Figure 1).

Potassium Boswellin and Boswellin 40% were then orally administered to two human volunteers who had spent the previous 16 hours fasting. 1 gram of Potassium Boswellin was given to Individual A and 1 gram of Boswellin 40% was given to Individual B. Both the Potassium Boswellin and the Boswellin 40% were suspended in 35 mi of milk and given to the subjects to consume. 5 ml of blood was withdrawn from the volunteers at intervals of 5,10,20,40,80, and 160 minutes.

The blood samples were collected into sterile centrifuge tubes and left for 120 minutes to retract the clot. The samples were then centrifuged to separate the serum. The serum was transferred to sterile 2 mi vials and stored at 0 C-4 C overnight.

The serum samples were then brought to room temperature. 1 ml of the serum was placed into a 10 ml stoppered volumetric flask and 1 ml of 3 N HCI was added to it. This mixture was then sonicated for 20 minutes to free the boswellic acid. The volume of the mixture was then brought to 10 ml with methanol and the resulting solution was sonicated for 10 minutes to extract the boswellic acids and to precipitate the serum proteins. This prepared sample was then transferred into capped centrifuge tubes and centrifuged at 4,000 rpm for 10 minutes. The serum proteins were precipitated as sediment and the clear supernatant was filtered through No. 1 filter paper.

The clear supernatants were then subjected to a HPLC assay, the results of which are shown in Figures 2-5. As can be plainly seen, the serum with Potassium Boswellin shows that a greater amount of boswellic acids have been absorbed by the subject's bloodstream, thereby demonstrating the efficacy of the present invention.



EXTRACT OF OLIBANUM (FRANKINCENSE GUM) IN THE FORM OF NANOPARTICLES, AND USE THEREOF
WO2006128634

[ Machine translation ]

The invention relates to a novel and improved nanoparticulate form of a frankincense gum extract, containing, inter alia, Boswellic acids and/or their derivatives. The nanoparticles have advantageous properties for use in the treatment of inflammatory diseases. Surprisingly, these advantages are obtained both in topical application and oral administration. When used in topical formulations, the nanoparticles are better absorbed by the skin than are known, tacky extracts, and they are thus suitable for the treatment, for example, of neurodermatitis and/or actinic keratosis and/or basal cell carcinoma and/or epithlioma and/or squamous cell carcinoma of the skin. For example, in soft gel capsules that dissolve in the small intestine, the nanoparticles have much improved bioavailability, which also considerably improves oral administration for treatment of inflammatory conditions. Finally, the nanoparticles can also be used for coating stents and implants.

0001] extract from olibanum (incense) in the form of nanoparticles and

[0002] using the same

[0003] The invention relates to a new and improved nanoparticulate form of a Olibanumextraktes (incense extract) containing, among other boswellic acids and / or derivatives thereof.

The dissolved Olibanumextrakt embedded in spherical particles having a three-dimensional size in the nanometer (nm) range.

The so-called nanoparticles have advantageous properties in terms of a use for treating inflammatory diseases.
Surprisingly these advantages are obtained both for a topical, an oral administration as well as a surface coating of implants.

The nanoparticles are absorbed better when used in topical formulations of the skin known as sticky extracts and thus suitable for the treatment of, for example, atopic dermatitis and / or actinic keratosis and / or basal cell carcinoma and / or squamous and / or squamous cell carcinoma of the skin.

For example, in enteric softgels show the olibanum nanoparticles significantly improved bioavailability, which also improves oral use in the treatment of inflammatory conditions significantly.

Finally, Olibanum nanoparticles can also be used for coating of implants (vessel joint, bone, tooth) and surgical sutures.

[0004] state of the art early in oriental folk medicine is the use of incense, primarily in India and in the Near East, for the treatment of various diseases, especially inflammation and rheumatic joint diseases known.
Even in recent times several medical applications have been found for incense or Olibanumextrakte and especially for boswellic acids and their derivatives.

Inflammatory responses are measures of the organism, which serve to remove the damaging tissue damages by causing foreign bodies or the damaged part of the tissue repair and replace tissue.

Hence, inflammation is a physiological process.

However, there are a number of situations in which functions of organs are disturbed by inflammatory processes, especially when they are shooting or chronic.

Inflammation is triggered by the release of so-called biochemical mediators of inflammation.

There are two types of different inflammatory mediators that are involved in the formation and maintaining inflammatory prostaglandins and leukotrienes.

The current therapy of inflammation occurs with drugs that are predominantly in a position called the arachidonic acid cascade, namely to block the part of the leads to the formation of Prostaglandiene.

The drugs used are among the steroidal and non-steroidal anti-inflammatory drugs.

The anti-inflammatory effects of these drugs is associated with significant side effects.

[0005] The anti-inflammatory effect of boswellic acids has been repeatedly published (Safayhi, H., et.
AI, Planta Medica 63, 487-493, 1997. J. Pharmacol. And Exp Ther, 261, 1143-46, 1992). Sashwati et al investigated by screening the human genome, the genetic basis of the anti-inflammatory effect of Boswellia in microvascular endothelial cells and found an inhibition of 5 -lipoxygenase, a key enzyme in the biosynthesis of leukotrienes. The research revealed that 3-O-acetyl-11-keto-boswellic acid is the most potent as 5-lipoxygenase inhibitor among the boswellic acids.

In addition, the boswellic acids prevented the TNF-alpha-induced expression of metalloproteinases and of mediators of apoptosis.

It was also the expression of  VCAM-1 and ICAM-1 suppresses Olibanumextrakte.

This research showed that Olibanumextrakt by influencing the mechanisms of inflammation Signalmecha anti-inflammatory effect (Sashwati, R., et al, DNA AND CELL BIOLOGY:. VoI 24, Number 4, 2005).

[0010] EP 552 657 A1 discloses that pure boswellic acid, the physiologically compatible salts borrowed, derivatives thereof and salts of derivatives or a herbal preparation containing boswellic acid can fight inflammation, caused by increased leukotriene formation.

It is suggested in the treatment of inflammatory joint diseases, epidermal lesions, allergic and chronic asthma, Endoxinschock, inflammatory bowel disease and chronic hepatitis with these compounds.

[0011] WO 90/01937 reports that a-and ss-Boswelliaacetat Boswelliaacetat and its analogs inhibit topoisomerase I and topoisomerase II.

Therefore, this document proposes to use the compounds for the treatment of various cancers.

[0012] WO 97/07796 uses boswellic acid, a physiologically acceptable salt, derivative, a salt of said derivative or a boswellic acid-containing herbal preparation for the prophylaxis and / or the control of diseases that are caused by increased Leukozytenelastaseoder Piasminaktivität.

Therefore, this document proposes to use the compounds in the treatment of diseases such as emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, cystic fibrosis, chronic bronchitis, glomerulonephritis and rheumatoid arthritis, and also to inhibit the growth and metastasis of many cancers.

[0013] WO 02/15916 discloses Dihydroboswelliasäuren, physiologically acceptable salts thereof, and hydrogenated extracts of boswellia.

It is proposed to use these compounds for prophylactic and / or therapeutic treatment of adverse physical and psychological conditions, especially of somatic, psychosomatic and mental disorders such as inflammatory processes, which are caused by increased leukotriene formation, Leukozytenelastaseoder Piasminaktivität.
The above diseases are, for example inflammatory joint diseases, epidermal lesions, allergic and chronic asthma, endotoxin, inflammatory bowel disease, chronic hepatitis, pulmonary emphysema, acute respiratory distress syndrome, shock lung, cystic fibrosis, chronic bronchitis, glomerulonephritis and rheumatoid arthritis as well as specific tumors and tumor metastases.

[0015] DE 101 21 252 A1 describes the treatment of acne, a hormone-induced inflammatory skin disease, the use of lipoxygenase inhibitors alone or in combination with other lipoxygenase inhibitors or with other anti-acne agents in a suitable pharmaceutical composition, in particular by oral and / or locally-applied topically.

[0016] In the publication U.S. 2004/0166178 A1 discloses the use of 3-O-acetyl-11-keto-boswellic acid is described in a formulation for topical application for relaxation of the skin and for the treatment of facial wrinkles.

[0017] In summary it can be said that incense and Olibanumextrakte is known as a traditional natural remedies or medicines to treat various physical and mental conditions.

Because of the versatility of the applicability of the good effect coupled with reduced side effects, there is a great need to provide Olibanumextrakte in an improved form, and this improved formulation for as many applications, such as topical and oral administration as well as for coating implants and should be suitable for surgical sutures.
To skin diseases

[0018] In the case of eczema (including atopic dermatitis, eczema atopic, eczema diffusa, eczema disseminated, eczema constitutionalis, endogenous eczema Besnier-prurigo) is a chronic or chronically relapsing, in their morphological aspect and overall process quite different types of inflammatory skin disease which is accompanied by severe itching.

The eczema is hereditary and often occurs together with other atopic diseases such as allergic rhinitis, allergic conjunctivitis and allergic bronchial asthma on.

Biochemically is neurodermatitis a fault in the humoral and cellular immunity, the infection is associated with a high activity of the skin.

The current treatment of these inflammatory skin disorder is often performed by means of the external application of glucocorticoids in the form of ointments or creams.

This inflammatory activity is indeed reduced, but the treatment is associated with significant side effects with cortisone.

[0019] The incidence of "light skin cancer," meaning Kanzerosen as actinic keratoses, basal cell carcinomas, squamous cell carcinomas and squamous fall, takes explosively in the temperate latitudes.

The "light skin cancer" is ten times more common than melanoma, the skin cancer known as black. Every seven years, double the number of cases. One of the causes is sun exposure and skin damage caused by UV radiation and the frequent use of tanning beds.

The actinic keratoses are now no longer classified as a precancerous condition, but as an early cancer.
Approximately every second German has over 60 years due to many years of UV light exposure to actinic keratoses.

Most actinic keratoses persist as long Carinoma in situ, whereas 20% show spontaneous remission or develop into invasive carcinomas spinozelläre.

There are now following therapeutic options: 1 Surgical removal (eg As excision, curettage, cryosurgery), with mostly 100% remissions are obtained. However, there remain scars and surrounding skin areas that were indeed exposed to the same UV exposure, remain untreated.

 2 Chemotherapies (eg As 5-fluorouracil or podophyllin) reach up to 85% remissions and can be applied areally.
However, they must be carried out over weeks, are painful and can leave scars and pigmentation.

[0021] 3 Photodynamic Therapy: After photosensitization by 5 - aminolevulinic acid cream light to destroy the tumor cells. Remissions and good cosmetic results can be achieved. For this, the procedure is painful phototoxic reactions are possible.

[0022] 4 Immunomodulators: For example, with imiquimod or diclofenac as a cream or gel remissions in up to 80% of cases can be achieved and the actinic keratoses can be removed without leaving any scars. The treatment is repeated, but it takes at least 12 weeks and requires a high level of patient compliance.

[0023] In the above-mentioned skin diseases is a high inflammatory activity with activation of inflammatory mediators, such as prostaglandins and the 5-lipoxygenase. In the skin lesions can be as in the basal cell carcinoma, squamous and squamous skin cells degenerate prove. By antiphlogistic drugs that interfere with the prostaglandin, such as diclofenac, remission can be achieved, but these drugs are known side effects.

Boswellic acids that occur from Olibanumharz in the extract have anti-inflammatory, antiproliferative and cytostatic effects.

The anti-inflammatory action based on inhibition of 5-lipoxygenase, in an essential enzyme for the synthesis of leukotrienes (see, for B. Safayhi et al., Mol Pharm 47, 1212-1216, 1995. Sailer et al, Arch Pharm 329, 54-56, 1996) and the inhibition of leukocyte elastase, as described in EP 854 709th

Furthermore, boswellic acids have a cytostatic effect.

It is reported more recently, of chemopreventive and therapeutic effects of acetyl-keto-boswellic acids in the treatment of various cancers.

This seems to be the inhibition of topoisomerase-1, alpha TopoisomeraseIl and induction of apoptosis through activation of caspase-3 and -8 play a key role by boswellic acids (Jian-Jun Liu, et. AI., Intern. J. of Molecular Medicine 10:. 501-505, 2002, Shao et al, Planta Medica 64, 328-331, 1998). These effects appear to be suitable as boswellic acids for treatment of tumors, as described in EP 871 437

[0024] Treatment of inflammatory and malignant skin diseases Olibanumextrakten and / or boswellic acids and derivatives thereof is generally known in the prior art. However, arises with the topical use of the extracts, the problem that they are typically sticky and thus have the property not to be absorbed by the skin and therefore can not operate in the deeper skin layers.

[0025] There is therefore a need, extracts of frankincense in a form more available for topical applications to provide that optimally penetrate into the skin to the skin in order to be pharmacologically active either topically or systemically.

Vascular disease

[0026] Atherosclerosis is the cause of heart attacks, strokes and peripheral vascular occlusive disease of the extremities and is a chronic inflammatory fibroproliferative disease of the arterial wall, which is associated with an impaired immune response.
Inflammatory processes, the inner wall of arteries, the intima, disturbed in their integrity and particularly loaded vessel sections, for example on vessel bifurcations occur injuries and lacerations of the intima.
Inflammatory cells in the lesions themselves are deposited as monocytes, macrophages, dendritic cells, mast cells and neutrophils.
Mast cells are transformed by taking up oxidized low-density lipoproteins (LDL) in foam cells and to form the "lipid core" of the so-called plaques, inflammatory ulcers in the vessel wall.
Reduce by chronic inflammation with activation of metalloproteinases, enzymes, connective tissue and collagen, the connective tissue sheath layer of the plaques is injured and the lipid-containing core of the plaques come in contact with the coagulation system of the blood, it forms very quickly Gerinnungspfropf which closes the vessel .
This process occurs in a coronary artery that supplied by the vascular portion of the heart muscle dies from lack of oxygen. A heart attack is the result. Atherosclerotic processes in the brain that trigger strokes.

[0027] The inflammation of the vessel wall are activated by inflammatory mediators, such as prostaglandins and leukotrienes released. Leukotrienes are formed via the 5-lipoxygenase cascade of inflammation. It has been shown that 5-lipoxygenase expressed in increasing concentrations at various stages of atherosclerosis in the arterial wall (Spanbroek, R.; PNAS, Vol 100, No. 3, 1238-1243, 2003). The authors proposed a new model of atherosclerosis in which mediated by the 5-lipoxygenase inflammatory activity in the vessel wall is the cause of the progression of atherosclerotic lesions.

[0028] Inflammatory markers in the blood of patients with atherosclerosis have elevated levels of C-reactive protein, interleukin 116, tumor necrosis factor alpha (TNF-alpha), a reduced antioxidant capacity, increased lipid peroxidation and increased homocysteine ??concentrations.
In the treatment of patients with coronary heart disease with statins, that lipid-lowering drugs, in addition to a reduction of the anti-inflammatory effects LDLCholesterinspiegels a reduction was observed with the C-reactive protein concentration.
This effect was accompanied by a significant reduction in the risk of sudden cardiac death and stroke and the significant decrease in the lipid core forming lipoproteins (LDL) and inflammatory activity has been attributed.

[0029] The treatment of atherosclerosis, coronary heart disease is classically with medications such as statins, beta-blockers, ACE inhibitors, and acetylsalicylic acid, which all require considerable side effects.

[0030] Olibanumextrakte point, as explained in detail above, anti-inflammatory and antiproliferative effects on cytostatic, which is also known from the prior art.
These effects make the extracts useful in the treatment of inflammatory processes and vascular proliferative diseases, arteriosclerosis, and side effects of conventional drugs can be avoided.

[0031] However, there is a need, extracts of frankincense in a more bioavailable form for oral administration to provide. implants

[0032] As an example, stents: percutaneous transluminal angioplasty (PTA) of blood vessels, especially the coronary artery angioplasty (PTCA) is a very common way to eliminate strictures or stenoses, which obstruct the blood supply of human organs.

Endovascular stents are used as a scaffold in order to prevent a sudden arterial occlusion in the angioplasty.
Stents may also reduce the restenosis rates as compared with a conventional balloon angioplasty.

Restenosis after stent implantation, however, provide at rates 20-30% remains a Problern in coronary arteries dar.
Restenosis is the result of massive blood vessel damage with induction of inflammation and endothelial cell proliferation stimuli for the use of a stent.

Rates of restenosis following stent implantation are also from the stent design and material dependent.
From WO 90/13332 and WO 91/12779 stent has become known, which are coated with anti-inflammatory drugs gerinnungsund to reduce restenosis rates.

The erfolgversprechensten drugs that may reduce restenosis rates effective agents include rapamycin (sirolimus (R)) and paclitacel (Taxol (R)).

[0033] Rapamycin is a macrolide antibiotic which has both anti-inflammatory and antiproliferative properties.
It prevents smooth muscle cell proliferation and reduces the inflammatory response induced by stent implantation by inhibition of proinflammatory cytokines (Suzuki et al., Circulation 104 (10), 1188-1193, 2001).

[0034] One of the disadvantages of the currently discussed eluting stents is the delayed epithelialization of the stent inner surface, so that the antithrombotic therapy to prevent must be in-stent thrombosis significantly prolonged time. There is thus a need to provide an alternative means which is suitable to coat stents.

[0035] The object of the invention is therefore to provide Olibanumextrakt in a form which can be used in pharmaceutical and / or cosmetic and / or for the coating of the implant surface, and thereby improves the corresponding means.

This improvement should be guaranteed for different application forms such as topical and oral administration.
In the area of ??topical application is to be achieved in that the or can be absorbed by the skin, the active compounds of the Olibanumextrakts better.

In the oral administration of Olibanumextrakt the active ingredient to be more bioavailable.

In the application for the coating of surfaces of implant treatment of vascular disease is to be provided for example by means of a stent in the form Olibanumextrakt within which makes the coating of the stent with the active compound or compounds of Olibanumextrakt possible.

[0036] These objects are achieved by the subject matter of the claims.

[0037] Surprisingly it was found that Olibanumextrakte in nanoparticulate form are perfectly suitable, on the one hand in formulations for topical administration and the other in formulations for oral administration significantly improve their properties.

When applied topically, the active ingredient (or active ingredients) is much better absorbed by the skin than is the case with the use of conventional extracts.

For oral administration, preferably in enteric soft gel capsules, the bioavailability of the active substance (or substances) is considerably improved.

It was also found that Olibanumextrakte in nanoparticulate form are an excellent way to coat implants such as stents or other (port system, joint prostheses, Herzschrittmaeher, dental pins, screws, plates, Kirschner wires).

Also has been found out that surgical sutures (eg As polyethylene), and indwelling indwelling, vascular catheters can be coated with Olibanumextrakt-Nanopartikenl.

The devices mentioned can cause foreign body reactions in the human body, which may be associated with inflammation and even with Granulombildungen.

Surprisingly, it has been found that the coating of the device with OlibanumNanopartikeln prevent foreign body reaction or can be counteracted.

Ultimately, it has proved advantageous to add as additive to Olibanumextrakt storage solutions for biological materials in nanoparticulate form.

These can be used in transport solutions for organs, as used for example in organ transplantation.
[0038] Olibanumextrakt can be obtained by, for example, ethanol, methanol, ether or chloroform extraction extraction of resin of olibanum. Preferably, such extracts are lipophilic.

[0039] According to a preferred embodiment of the invention the Olibanumextrakt with acetyl-11-keto-boswellic acid is enriched ss.

Optionally, the hydrogenation of incense, and the physiologically acceptable salts and derivatives, as well as hydrogenated Olibanumextrakte can be used.

Suitable [0040] According to the invention as an additive containing boswellic acids are also herbal extracts, their hydrogenation, boswellic acids, physiologically acceptable salts of the boswellic acids, derivatives of boswellic acids, herbal preparations containing boswellic acid or acetyl-11-keto-boswellic acid ss-containing plant extracts.
Also suitable are hydrogenation products of other ingredients of the incense, such as from the other Tirucallensäure or triterpenoid compounds, salts or derivatives thereof as well as plant extracts containing these compounds.
According to the invention are suitable as an additive continue the hydrogenation of acetyl-11-keto-boswellic acid or ss-ss-11-keto-boswellic acid or ss-boswellic acid, the latter may contain small amounts of alpha or gammaBoswelliasäure.

Also suitable are hydrogenation of ss-boswellic acid, Boswelliasäureformiat ss, ss-boswellic acid, acetyl-ss-boswellic acid, but also of the boswellic acids and derivatives of boswellic acids, which are described in DE-A 42 01 903, of which reference is made to the will.

[0041] boswellic acids, in particular acetyl-11-keto-boswellic ss can, in a known manner to be obtained from boswellic acid-containing plants.

Suitable Boswelliaarten are: Boswellia serrata, Boswellia carteri, Boswellia sacra, Boswellia papyrifera, Boswellia frereana, boswellia or Boswellia thurifera glabra, but also other members of the Boswellia family, or Commiphora family can be used.

[0042] As inventive hydrogenation can Dihydroboswelliasäuren, their physiologically acceptable salts, derivatives thereof, and physiological salts of derivatives, in particular ss-dihydro-boswellic acid acetate, ss Dihydroboswelliasäure formate, ss Dihydroboswelliasäure methyl ester, acetyl-ss-dihydroboswelliasäure, alpha dihydro-boswellic acid, acetyl-a-formyl-a-dihydroboswelliasäure and dihydroboswelliasäure be used.

[0043] According to the invention are also suitable keto Dihydroboswelliasäuren their physiologically acceptable salts, derivatives thereof and physiological salts of the derivatives, especially acetyl-11-keto-ss-dihydroboswelliasäure, 11-keto-ss-dihydroboswelliasäure or formyl-11-keto-ss -dihydroboswelliasäure.
The compounds useful according to the invention can be obtained by hydrogenation, preferably by catalytic hydrogenation.

The hydrogenation of these compounds is carried out in a manner known in the art, preferably so that the backbone of the compound is selectively hydrogenated.

Such a method is described for example in WO 02 / 15916th

[0044] For the preparation of the inventive pharmaceutical composition may further contain a hydrated plant extract is from incense, for example, ethanol, methanol, chloroform extraction, ether extraction, or obtained may be used.

[0045] The Olibanumextrakte used in the invention include, in particular ss-boswellic acid and / or acetyl-ss-boswellic acid and / or acetyl-11-keto-ss-boswellic acid and / or 11-keto-ss-boswellic acid and optionally with acetyl-11- beta.-keto-boswellic acid at levels higher than the natural content enriched.

[0046] In accordance with the invention physiologically acceptable salts, especially the sodium, potassium, ammonium, magnesium and calcium salts of the above compounds are understood.

Derivatives such as in particular Ci-C6 - alkyl esters of Dihydroboswelliasäure understood, in which the carboxyl group of the Dihydroboswelliasäure was esterified with a corresponding alcohol.

Such Dihydroboswelliasäurealkylester are for example the methyl ester, ethyl ester, n-propyl, iso-propyl, n-butyl, iso-butyl esters and the tertButylester Dihydroboswelliasäuren.

It is also possible that the hydroxyl group of the Dihydroboswelliasäure is esterified with a physiologically acceptable carboxylic acid, for B. a dbis C2o, in particular having a CRC8 carboxylic acid, in particular formic acid or acetic acid.

Herbal preparations that can be used for the preparation of the novel Olibanumextrakte are commercially available, for example from the company PL-Thomas, New Jersey under the name 5-Loxin (TM).
This is a standardized Olibanumextrakt of Boswellia serrata, at least 30% of the acetyl-11-keto-ss-boswellic acid contains.

[0047] According to the invention, however, can also Olibanumextrakte and their hydrogenation products are used by other preparations, in particular according to the invention can also hydrogenation synthetically manufactured or natural way derived ingredients of incense, especially acetyl-11-keto-ss-boswellic acid and / or 11 - beta.-keto-boswellic acid and / or ss-boswellic acid, optionally in admixture with a-und/oder yBoswelliasäure and / or several of the derivatives according to the invention are preferably used the boswellic acid, as described above, to produce the drug.

[0048] According to the invention, the medicament in addition to the herein defined, based on incense ingredients or other active ingredients, especially other herbal ingredients contained.

[0049] According to the invention is brought into a nanoparticulate form with one or more of the optional additives described above, the Olibanumextrakt.

Preferably, the nanoparticles have a size in the range of 30 to 400 nm, preferably 60 to 200 nm, more preferably from 100 to 200 nm.

Those skilled in the art will vary depending on use of the medicine anvisierter known per se and suitably produce nanoparticles.

[0050] Since the Olibanumextrakt, especially the hydrogenated Olibanumextrakt and especially the hydrogenated boswellic acids and their derivatives and salts have a very low toxicity, their compatibility is generally good.
Your dosage can be easily selected by the treating physician according to the severity of the condition being treated and other factors such as the duration of the disease, possible known incompatibilities of the patient's general condition of the patient, etc..

The drug according to the invention can be formulated so that it is in unit doses one or more times daily, in particular mono-to four times a day can be administered.

[0051] For topical application, the inventive nanoparticles can be incorporated into dermatocosmetic ointment bases, which can be applied several times daily to the affected skin.

The inventive pharmaceutical compositions may be, for example, in solid, semisolid, or liquid form.
Suitable creams, ointments, gels, lotions, etc.

[0052] For oral administration come into consideration tablets, granules, capsules, solutions, etc., which include pharmaceutically acceptable additives in addition to the invention nanoparticles.

Furthermore, the pharmaceutical compositions may be in a manner known in the art as liquid compositions for oral administration.

Preference for oral administration enteric softgels are thin.

[0053] The invention is not to be bound by the following statement, but probably have the novel nanoparticles of the active substance (or substances) in enteric softgels to a significantly improved bioavailability, since the nanoparticles probably similar transport mechanisms in the intestine as the Phosphatidylcholinmatrix triglycerides are absorbed via chylomicrons.

Other examples of suitable formulations and methods for their preparation can be found in DE-A 44 44 288 and DE-A 44 45 728, to the extent fully incorporated herein by reference.

[0054] Finally, the invention nanoparticles of the active ingredient (or ingredients) for coating medikamenteneluierenden implants, such as stents, are suitable.

By the inhibitory effect on the proliferation of smooth muscle cells in the vessel wall and by inhibiting the inflammatory processes counteract the novel nanoparticles of in-stent restenosis.

According to the international medical literature, it comes with the conventional stent within the first six months in 30% of cases a stent closure or to an in-stent stenosis.

For nanoparticles coated with the inventive stent is a high probability that this closure rate can be significantly reduced.

[0055] By inhibiting effect on the proliferation of connective tissue cells, and by inhibiting the inflammatory processes as an additive to implant erfindungsmässen OlibanumNanopartikel Cement (bone cement) act against the surface of implants of Fremdkörpergranulombildung and loosening of joint implants by Entzündungsund against degeneration processes.

[0056] Examples

[0057] Example 1:

[0058] Use of the nanoparticles according to the invention as a topical cream to treat inflammatory skin diseases,

[0059] 1-5% (relative to the ointment base) of the novel nanoparticles are applied morning and evening to the affected skin and gently massaged.

Inflammation is a visible reduction in pilot studies in actinic keratosis, eczema and psoriasis already detectable after one week.

For example, the inflammatory lesions were completely healed after a treatment period of 6 weeks at a cohort of 5 patients with actinic keratoses in 3 patients.

In one patient the result was confirmed histologically.

In 2 patients, the skin lesions were significantly improved.

[0060] Example 2:

[0061] possibility of enhancing the effect of

[0062] In inflammatory skin diseases according to the invention nanoparticles were prepared as described in Example 1 above, is applied. In addition, activation was:

[0063] 1 A soft laser, 785 nm, laser shower (from MKW Laser System) with 14 x 10 mW power, 5 minutes in direct skin contact times per two weeks and

[0064] 2 With water-filtered infrared-A (from Hydrosun) for 20 min at 30 cm distance, two per week, performed once. The infrared activation of nanoparticles according to the invention was carried out 2 times a week.
By activation with infrared led to a much faster effect.

The postulated mechanism could be a direct activation of boswellia triterpenes by energy absorption and improve the penetration properties of the skin by a low-thermal radiation.



Optimized frankincense and myrrh treating process
CN1349813  

[ Machine translation ]

The optimization treatment process of the Chinese medicinal materials of frankincense and myrrh includes the following steps: pulverizing, dissolving and extracting to obtain volatility component, then using beta-CD to make mixing and inclusion, cooling and filtering to obtain the invented frankincense and myrrh extract. Before inclusion and after one combined image structure of the volatile oil and beta-CD gets obviously change, so that when the frankincense and myrrh are used, it can reduce irritation to gastrointestinal tract, and can reduce production of adverse reactions of abdominal pain, nausea, vomiting, diarrhea, dyspepsia and anoraxia, etc. to further raise medicine effect of frankincense and myrrh and raise the preparation quality.

The invention relates to the field of medicine, in particular to a frankincense, myrrh optimization processes...

The object of the present invention can be achieved by the following measures:
One kind of frankincense, myrrh optimized treatment process is frankincense, myrrh become crushed particles With petroleum ether, dissolved, extracted until a colorless, volatile petroleum ether and volatile oil obtained, and then With ß-CD solution mixing, cooling, filtration can be.

The invention will be further described in detail with reference to Examples:

process: take frankincense, myrrh, to crush a particle with petroleum ether
Solvent dissolved, extracted with Soxhlet extractor pumping until colorless, and then in a water bath hood
Within volatile petroleum ether to obtain volatile oil and seal it back; Another ß-CD was dissolved in distilled
Water and placed DF-101 collector-type magnetic stirrer, adding essential oil dissolved in ethanol,
Maintaining a predetermined temperature, mixing a predetermined time, and make up water, then in the refrigerator to
Chilled for 24 hours, with a dry pump suction filter, washed with a small amount of ethanol, 60 ? dried for 2
Hours, weighing, measuring oil content, and calculate the oil utilization and yield...

The results show that the temperature of the oil contained utilization rate and the oil has a significant impact on the yield of No significant effects feed ratio and stirring time of oily rate has a significant impact on oil profits With a yield rate and a significant effect


   
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